The long-term goal for this research is the development of alternate therapeutic strategies that prevent the inflammatory changes associated with neurodegeneration. The immediate goal of this project is to characterize the molecular mechanisms of calcitonin gene-related peptide (CGRP) receptor activation that initiates signaling networks leading to increased production of pro-inflammatory compounds. The neuroactive peptide, CGRP is released from peripheral and central nerve terminals upon sensory activation caused by damaged tissue. CGRP potently initiates vascular changes that are a hallmark of neurogenic inflammation. However, CGRP released from sensory nerve endings are suggested to initiate more than just a direct vasodilator effect on vascular smooth muscle during an inflammatory event. Increasing evidence suggests that neurogenic inflammation orchestrated in part by microglial cells, is a major pathophysiological component of neurodegenerative disease. An increased expression of cyclooxygenase-2 (COX-2) by CGRP has been shown in vitro using the human microglia progenitor cell line, THP-1. Selective generation of prostaglandins by COX-2 has been demonstrated to cause a hypersensitive response in neurons. Moreover, chronic induction of inflammatory cytokines (e.g., TNF-a) has been implicated in the pathophysiology of neurodegeneration. Conversely, application of CGRP to LPS activated THP-1 cells inhibits the production of TNF-a suggesting an anti-inflammatory role for CGRP. These opposing observations implicate CGRP as an important modulator of selective neuroinflammatory signaling possibly initiated through distinct receptor subtypes. However, the bioavailability and protease sensitivity of receptor ligands limits exploration and characterization of CGRP effects in vivo. This research is guided by the hypothesis that detailed insights, into the molecular mechanisms of ligand dependent receptor signaling will provide information for the rational development of CGRP receptor mediated therapeutics. Aim one will describe the CGRP mediated signal transduction pathways that lead to production of inflammatory compounds. Aim two will characterize the structure-function relationships of CGRP receptor activation from which a working molecular model of the receptor can be developed. Aim three will challenge this molecular model using altered CGRP ligands to authenticate binding contacts and to categorize functions of specific CGRP receptor amino acids. Completion of these specific aims will further our understanding of molecular signaling mechanisms initiated by CGRP receptor activation that participate in selective inflammatory responses implicated in the pathophysiology of neurodegenerative diseases.